ASD. Conversely, other de novo CNVs may have weaker effects, requiring contributions from additional loci (for example additional risk haplotypes, or other CNVs), or environmental risk factors, for the burden of contributory factors to cross a risk threshold and result in an ASD phenotype. In three of the eight families (6 ASD and 2 ID) that carry putative PTCHD1 missense mutations (Families 8, 9 and 10), we have identified other CNVs involving genes that may also contribute to the phenotype. In Family 9, in addition to the I173V substitution, we found a de novo ~1.0 Mb loss at 1p21.3 resulting in deletion of the entire DPYD gene (MIM 274270), encoding dihydropyrimidine dehydrogenase (DPD) (3). Complete DPD deficiency results in highly variable clinical outcomes, with convulsive disorders, motor retardation, and mental retardation being the most frequent manifestations, and autistic features occasionally reported (27). In this family, a balanced translocation, t(19;21)(p13.2; q22.12) is also present in the proband, but is inherited from the unaffected mother and shared with an unaffected sister (see Supplementary Materials). In Family 10, which shows the V195I substitution in PTCHD1, we have previously reported a 66 Kb de novo loss at 7q36.2 that results in deletion of the
